Phthalocyanines have great promise as sensitizers for photodynamic therapy (PDT) of cancer. We have shown that certain tertiary and quaternary amines linked to the metal can improve the cellular uptake and photosensitizing properties of these compounds. The proposed research will test the hypothesis that amine moieties linked to appropriate metals within the phthalocyanine ring can provide highly efficient photosensitization. Aim I: Based on our preliminary studies of new phthalocyanines, selected additional compounds will be synthesized with potentially greater photosensitizing efficiency. Aim II: The phthalocyanines will be screened for photosensitizing efficiency in vitro; the most active of these will be tested in RIF-l tumors in vivo for dark toxicity, for pharmacokinetics, and for the efficiency with which they photosensitize the tumors to red light irradiation. The mechanisms by which the new phthalocyanines act in vivo will be explored by comparison of the kinetics of loss of tumor cell clonogenicity in vitro with tumor ablation in vivo. Aim III: Drugs varying in photosensitizing activity will be compared with respect to damage induced in the plasma membrane, mitochondria, and nuclei of treated cells. Aim IV: To investigate processes involved in PDT cytotoxicity, (a) direct tumor cell killing and (b) the altered environment of tumors following PDT will be studied by exposing PDT-treated cells to growth- limiting conditions in vitro. Finally, mechanics of the marked enhancement of photodynamic cell killing by the ionophore nigericin and possibly other membrane-active agents will be investigated. These studies should identify new phthalocyanines with good potential as photosensitizers of PDT, elucidate important aspects of the mechanisms of photosensitization of cells and tumors, and contribute to an understanding of the structure- activity relationships for this class of compounds.